Dialysis is a well established treatment technique for patients having kidney malfunction. The dialysis treatment artificially replaces the functions of the kidney. There are two distinct types of dialysis; hemodialysis and peritoneal dialysis.
Hemodialysis involves withdrawing blood from the body and cleaning it in an extracorporeal blood circuit, and then returning the cleansed blood to the body. The extracorporeal blood circuit includes a dialyzer which comprises a semipermeable membrane. The semipermeable membrane has a blood side and a dialysate side, and waste substances and excess fluid are removed from the blood passing on the blood side of the semipermeable membrane through the semipermeable membrane over to the dialysate side of the semipermeable membrane.
Hemodialysis may be performed in three different treatment modes, hemodialysis, hemofiltration, and hemodiafiltration. Common to all three treatment modes is that the patient is connected by a blood line to the dialysis machine, which continuously withdraws blood from the patient. The blood is then brought in contact with the blood side of the semipermeable membrane within the dialyzer in a flowing manner.
In hemodialysis, an aqueous solution called dialysis fluid is brought in contact with the opposite membrane surface, the dialysate side, in a flowing manner. Waste substances (toxins) and solutes are removed/controlled mainly by diffusion. Excess fluid is removed by applying transmembrane pressure over the semipermeable membrane. Solutes and nutrients may diffuse in the opposite direction from the dialysis fluid, through the semipermeable membrane and into the blood.
In hemofiltration, no dialysis fluid is brought in contact with the dialysate side of the semipermeable membrane. Instead only a transmembrane pressure is applied over the semipermeable membrane thereby removing fluid and waste substances, from the blood through the semipermeable membrane wall and into the dialysate side thereof (convective flow). Fluid and waste substances are then passed to drain. To replace some of the removed fluid, a correctly balanced electrolyte/buffer dialysis fluid (also named infusion fluid or replacement fluid) is infused into the extracorporeal blood circuit. This infusion may be done either upstream the dialyzer (pre-infusion mode) or downstream the dialyzer (post-infusion mode) or both.
Hemodiafiltration is a combination of hemodialysis and hemofiltration, a treatment mode that combines transport of waste substances and excess fluids through the semipermeable wall by both diffusion and convection. Thus, here a dialysis fluid is brought in contact with the dialysate side of the semipermeable membrane in a continuously flowing manner, and a dialysis fluid (also named infusion fluid or replacement fluid) is used for infusion into the extracorporeal blood circuit in pre-infusion mode, post-infusion mode or both.
For many patients, hemodialysis is performed for 3-5 hours, three times per week. It is usually performed at a dialysis centre, although home dialysis is also possible. When home dialysis is performed patients are free to perform dialysis more frequently and also in more gentle treatments with longer treatment times, i.e. 4-8 hours per treatment and 5-7 treatments per week. The dose and treatment times may be adjusted due to different demand of the patients.
In the case of patients suffering from acute renal insufficiency, a continuous treatment, throughout a major portion of the entire day for up to several weeks, a continuous renal replacement therapy (CRRT), or intermittent renal replacement therapy (IRRT) is the indicated treatment depending on the patient status. Also here the removal of waste substances and excess fluid from the patient is effected by any or a combination of the treatment modes hemodialysis, hemofiltration and hemodiafiltration.
In a peritoneal dialysis treatment a hypertonic dialysis fluid is infused into the peritoneal cavity of the patient. In this treatment solutes and water is exchanged in the capillary vessels of a patient's peritoneal membrane with said hypertonic dialysis fluid. The principle of this method is diffusion of solutes transferred according to the concentration gradient and water migration due to the osmotic differences over the peritoneal membrane.
The dialysis fluids used in all the above dialysis techniques contain mainly electrolytes like sodium, magnesium, calcium, potassium, an acid/base buffer system and optionally glucose or a glucose-like compound. All the components in dialysis fluids are selected to control the levels of electrolytes and the acid-base equilibrium within the blood and to remove waste materials from the blood.
Dialysis fluids are today prepared from different types of concentrates. These may be liquid concentrates of different degree of concentration, where the acid/-electrolyte part is separated from the buffer part.
The concentrates may further be provided in highly concentrated volumes of 1-8 L in bags, or in more diluted concentrated volumes of 5-20 L in canisters. The bags may be for bedside use, for mixing within a fluid preparation unit into a ready-to-use dialysis fluid.
The concentrates may also be provided as dry concentrates for dilution into liquid concentrates and further mixing within a fluid preparation unit into a dialysis fluid.
Concentrates may also be prepared in central tanks in volumes of typically 300-1000 L.
Alternatively, the concentrates illustrated herein may be provided as liquid concentrates divided between different compartments within a multi-compartment bag. These liquid concentrates are then mixed to prepare the ready-to-use dialysis fluid. This mixing may be performed by breaking a seal between the different compartments, but it may also be performed by having the different liquid concentrates being led from the different compartments to a fluid preparation unit for mixing therein into a dialysis fluid. For example, the multicompartment bag may comprise the citrate containing concentrate in one compartment while electrolytes like calcium and magnesium are kept in a separate compartment.
As mentioned above, the dialysis fluid contains an acid for the acid/base buffer system. Historically the acid used within dialysis fluids has been acetic acid. However, in recent years citric acid has emerged as an alternative to acetic acid in dialysis fluids. While increased plasma levels of acetate may induce symptoms like general malaise, intradialytic hypotension and nausea, citrate is a natural source of energy for all cells and part of the acid-base regulation in the body. In addition, citrate is an anticoagulant and antioxidant with anti-inflammatory properties and may improve patient treatment tolerance.
However, clinical trials have shown that it is not just to replace acetic acid with citric acid. Citric acid has specific effects that need to be taken into consideration, namely its ability to form a complex with electrolytes within the dialysis fluid. This complex formation has to be compensated for when deciding on the concentrations of all the components within the dialysis fluid.
Heparin is used as an agent for anticoagulation during dialysis. Most common way of administration is by infusion of heparin, or alternatively as a bolus dose prior the start of the dialysis treatment. However, for some patients, there are drawbacks with heparin infusion like heparin induced thrombocytopenia (HIT) and increased risk of systemic bleeding in the patient.
Heparin is commonly used as anticoagulation agent in the hemodialysis methods described above but due to its drawbacks citrate has been introduced and developed as an alternative anticoagulation agent in hemodialysis.
To achieve the desired anticoagulation effect in the extracorporeal circuit a concentration of citrate in the blood of about 3 mM shall be achieved. However, today dialysis fluids comprising a concentration of citrate of only about 1 mM is commercially provided. To achieve a more complete anticoagulation, heparin must be added and act in combination with the citrate or alternatively the concentration of citrate in the dialysis composition raised. As described above, the dialysis fluid is provided as a two-, or multi-part solution before its use as dialysis solution. The two-part solution comprises an acid solution and a base solution. However, the acid solution of these two-part solutions comprises components which may form complex and precipitate in the concentrate solution. The both solutions are mixed to form a neutral and for patient compliant solution.
In WO01/21233 A1 a high citrate dialysate and uses thereof is disclosed. The application discloses a dialysate composition comprising citrate at a concentration ranging from 2.4 to 20 mEq/L (equals 0.8-6.67 mM citrate), calcium at a concentration ranging from 2.5 to 5 mEq/L (equals to 1.25-2.5 mM calcium), and magnesium at a concentration ranging from 1 to 2 mEq/L (equals 0.5-1.0 mM magnesium).
The document does not disclose an acid concentrate comprising citric acid and citrate in specific ratios.
In U.S. Pat. No. 5,252,213 it is described a dry dialysate composition comprising citrate. The dry composition may be in form of a dry mixture, pellet or tablet. The dry composition comprises an acid, a bicarbonate and a salt. The acid is preferably citric acid. After dissolving the dry composition a dialysate comprising from about 130 to about 150 mEq of Na, from 0 to about 4.0 mEq of K, from about 2.0 to 3.5 mEq Ca, from 0 to about 1.5 mEq Mg, from about 25 to about 45 mEq bicarbonate, from 0 to about 2 g glucose, and from about 90 to about 120 mEq chloride ion. The citric acid is added at a concentration from about 2 to 12 mEq, and an acid pH of the dialysate may be obtained. The components are dissolved stepwise, and by that a chemical environment is created which prevents the formation of insoluble precipitates such as calcium salts. There is no disclosure of a specific ratio of citric acid and citrate present in the dialysate.
Consequently, there is a need to increase the content of citrate in the dialysis fluid, with the purpose to replace the heparin. Also, there is a need to increase the patient compliance for those who not accept heparin.
It may seem to be an easy action to just replace the heparin by adding corresponding amount of citrate. However, this replacement has been shown to be more complicated than just a simple replacement, due to precipitations of complex formed of citrate and divalent ions like calcium ions and magnesium ions commonly present in the dialysis fluids.
By the present invention it has been shown that by thorough elaboration of parameters it has been possible to increase the concentration of citric acid and citrate in the acid concentrate dialysis solution and to avoid precipitation of undesired complex.